Our long term objective is to understand the basis of the selection of the T cell receptor during thymocyte ontogeny. Mature, peripheral helper and killer T cells recognize foreign antigens as peptides fragments presented in a groove on the major histocompatibility complex encoded class II and class I molecules respectively. The T cell receptor contact sites on the peptide and on the self presenting molecule. The histocompatibility loci are extremely polymorphic. The various alleles bind different peptides and have different T cell receptor contacts. To ensure T cell recognition of foreign peptide is as efficient as possible, the thymic (self) histocompatibility molecules select which clones for immature T cells survive and populate the periphery. We propose to study this process of thymus selection using a range of closely related mutant self molecules (Kb mutants) and peptide antigens derived from ovalbumin and other class I Kb-restricted antigens such as Vesicular Stomatitis virus nucleocapsid protein. Knowledge gained in this area could have an immediate impact on the design of bone-marrow transplantation therapies. The information is also part of our understanding the T cell response to any infectious agent and in autoimmune diseases.